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Starting materials of phosphasugars, 1-phenyl-2-phospholene 1-oxides, were prepared from dienes and phenylphosphonous dichloride (dichlorophenylphosphine). Several substituted novel phosphasugars (3- or 4-halo-substituted)-1-phenyl-2-phospholene 1-oxides as well as 1-phenyl-2-phospholane 1-oxides were prepared from 2-phospholenes. The synthesized compounds were evaluated for their antitumor activities against the leukemia cell lines (U937 and K562) by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. 2,3,4-Tribromo-3-methyl-1-phenylphospholane 1-oxide showed superior antitumor activity against U937 and K562 cell lines in a comparative evaluation with Glivec. The analysis by flow cytometry implied that 2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide induced apoptosis to leukemia cell lines.

Phospha sugars were prepared by a novel synthetic route starting from phosphorus heterocyclic compounds, 2-phospholenes. The anhydro- and deoxy-phospha sugar derivatives have been revealed to have potential anticancer activities against human leukemia of K562 and U937 cell lines. In this article, deoxybromophospha sugars with different numbers of bromo substituents were prepared, and their anticancer activities were evaluated by MTT method. The order of the activities depending on the number of bromo substituent was first revealed, and trideoxytribromotetrofuranose type phospha sugar [2,3,4-tribromo-3-methyl-1-phenylphospholane 1-oxide (4: TBMPPAO)] was the most active among these phospha sugars prepared. Diasteromers of dideoxydibromotetrofuranose-type phospha sugar [2,3-dibromo-3-methyl-1-phenylphospholane 1-oxide (2: DBMPPAO)] were separated into four components, and the structure as well as the character of each component was assigned by spectral and chromatographic data as well as by MTT met...

Several new classes of deoxy phospha sugar derivatives, analogs of normal sugar derivatives, were conveniently synthesized using 1‐methoxy‐2‐phospholene 1‐oxide as a starting material. All compounds were structurally characterized by their spectral data, and stereochemistry was determined by spectral and X‐ray crystallographic analyses.

An x-ray crystallographic analysis was carried out for Boc-(Aib-DeltaZPhe)4-Aib-OMe (1: Boc = t-butoxycarbonyl; Aib = alpha-aminoisobutyric acid; DeltaZPhe = Z-alpha,beta-didehydrophenylalanine) to provide the precise conformational parameters of the octapeptide segment -(Aib-DeltaZPhe)4-. Peptide 1 adopted a typical 3(10)-helical conformation characterized byphi= +/-55.8 degrees (50 degrees -65 degrees),psi= +/-26.7 degrees (15 degrees -45 degrees), andomega= +/-179.5 degrees (168 degrees -188 degrees) for the average values of the -(Aib-DeltaZPhe)4- segment (the range of the eight values). The 3(10)-helix contains 3.1 residues per turn, being close to the "perfect 3(10)-helix" characterized by 3.0 residues per turn. NMR and Fourier transform infrared (FTIR) spectroscopy revealed that the 3(10)-helical conformation at the atomic resolution is essentially maintained in solution. Energy minimization of peptide 1 by semiempirical molecular orbital calculation converged to a 3(10)-helical conformation similar to the x-ray crystallographic 3(10)-helix. The preference for a 3(10)-helix in the -(Aib-DeltaZPhe)4- segment is ascribed to strong inducers of the 3(10)-helix inherent in Aib and DeltaZPhe residues-in particular, the Aib residues tend to stabilize a 3(10)-helix more effectively. Therefore, the -(Aib-DeltaZPhe)4- segment is useful to rationally design an optically inactive 3(10)-helical backbone, which will be of great importance to provide novel insights into noncovalent and covalent chiral interactions of a helical peptide with a chiral molecule.

An efficient method is described in the synthesis of several novel deoxy phospha sugar pyrimidine nucleosides in racemic form, analogs of normal sugar nucleosides, in high yields by treatment of (±)-2-aminophospholane 1-oxide with several, α-cyano-, -acetyl-, -ethoxycarbonyl-β-ethoxy-N-ethoxycarbonylacrylamides.

Several novel phospha sugar nucleosides, analogs of normal sugar nucleosides, were synthesized from a phospholene 1-oxide derivative. Bromination of a phospholene precursor in aqueous organic medium gave regio diastereomers, the threo and erythro bromohydrins 3 (1-bromo-1,3,4-trideoxy-1,4-C-[(R,S)-phenylphosphinylidene]-glycero-tetrofuranose). Further substitution of the threo isomer 3a with sodium azide led to its corresponding azidophospholane 4 (1-azido-1,3,4-trideoxy-2-methyl-1,4-C-[(R)-phenylphosphinylidene]-beta-D-glycero-tetrofuranose). 1,3-Dipolar cycloaddition of 4 with various electron-deficient and electron-rich alkynes afforded triazole derivatives that are nucleoside analogues. The strong electron-withdrawing phosphoryl group in the hemiacetal ring exerted no effect over reaction regioselectivity of the 1,3-dipolar cycloaddition, but steric effects of the alkynes played a vital role on the selectivity, since the regioisomer ratios and the rates and yields of cycloadducts changed as the bulkiness of the substituents on the acetylene changes. Structures of all compounds were unequivocally confirmed by 1H, 13C, and 31P NMR and mass spectral studies. Single crystal X-ray crystallographic analysis of some derivatives allowed determination of configuration of the phospha sugar nucleosides.

In this paper we attempted to reveal how a large β-substituent (pyrenyl group) of dehydroresidue affects the structural and conformational preferences of (Z)-β-substituted α,α-dehydroalanine. An X-ray crystallographic analysis was carried out for Boc–L-Ala–ΔZPyr–L-Val–OMe (Boc = t-butyloxycarbonyl; OMe = methoxy) possessing a novel (Z)-β-(1-pyrenyl)dehydroalanine (ΔZPyr) residue. Single crystals were obtained by slow evaporation from an ethanol solution in the monoclinic space group P21. The bond lengths and bond angles of the ΔZPyr residue were essentially similar to other β-substituted dehydroalanines. The tripeptide took a type II β-turn conformation involving an intramolecular hydrogen bond between CO(Boc) and NH(Val), like small peptides possessing a (Z)-β-(1-naphthyl)dehydroalanine or a (Z)-β-phenyldehydroalanine residue. The similarity between ΔZPyr and other dehydroalanines in structural property and conformational preference should be responsible for the non-planarity of the ΔZPyr residue to give...

An X-ray crystallographic analysis was carried out for Boc-(Aib-ΔZPhe)2-Aib-OMe 1 and Boc-L-Pro-(Aib-ΔZPhe)2-Aib-OMe 2 (Aib = α-aminoisobutyric acid; ΔZPhe = α,β-dehydrophenylalanine; Boc = tert-butoxycarbonyl; OMe = methoxy) to provide detailed conformational data for oligopeptides possessing an -(Aib-ΔZPhe)2- segment. Both peptides adopted a typical 310-helical conformation characterized by = 52.8°, = 29.3°, and = -173.8° for the average values of the four residues of the -(Aib-ΔZPhe)2- segment in peptide 1, and = 54°, = 27°, and = -175° for those in peptide 2. The preference for a 310-helix in the -(Aib-ΔZPhe)2- segment is ascribed to the presence of Aib and ΔZPhe residues being strong inducers for the formation of a 310-helix. In peptide 2, the N-terminal L-Pro residue adopted a semiextended conformation, leading to a left-handed screw sense for the following achiral segment. This result was also supported by conformational energy calculation, in which the L-Pro residue leading to a left-handed 310-helical segment prefers a semiextended conformation rather than a right-handed helical conformation.

A new type of designed and functionalized ligand for a lanthanide ion based on dendritic architecture was synthesized. The dendrimers, which contain four and twelve glucose moieties on the molecular surfaces, were readily synthesized with good yields in every step. The NMR and GPC analyses precisely demonstrated successful constructions of the dendritic structures, while the formations of gadolinium chelates were deduced on the basis of HPLC study.

To understand how chemical structure of beta-substituted alpha, beta-dehydroalanine (particularly size and pi conjugation of beta substituent) affects conformational property, x-ray crystallographic analysis was performed on Boc-Ala-Delta(Z) Nap-Val-OMe [Boc: t-butoxycarbonyl; Delta(Z) Nap: (Z)-beta-(1-naphthyl)dehydroalanine; OMe: methoxy] having the naphthyl group as a bulky beta substituent. Single crystals were grown by slow evaporation from an ethanol solution in the triclinic space group P1 with a = 9.528 (3) A, b = 12.410(4) A, c = 5.975(2) A, alpha = 96.77(3) degrees, beta = 102. 81(2) degrees, gamma = 88.74(3) degrees, V = 684.1(4) A3, and Z = 1. Phase determination was carried out by a direct method (SHELEXS), and the final structure was refined to R = 8.1% and R(w) = 9.0% for 1964 observed reflections. The bond lengths and bond angles of the Delta(Z)Nap residue, characterized by a sp(2) hybridized C(alpha) atom, did not differ from those of other dehydroresidues such as Delta(Z) Phe, Delta(Z) Leu, and DeltaVal essentially. The peptide backbone took a type II beta-turn conformation involving an intramolecular hydrogen bond between CO(Boc) and NH(Val), similar to di- or tripeptides containing a Delta(Z) Phe or Delta(Z) Leu residue in the second positions. Here the naphthyl group was found to be nonplanar [chi(2) = 55(1) degrees ] relative to the C(alpha)==C(beta)==C(gamma) plane. The nonplanarity was supported by conformational energy calculation. The molecular packing was stabilized by two kinds of intermolecular hydrogen bonds and van der Waals interactions. Naphthyl groups were arranged in a partially overlapped face-to-face orientation with a center-to-center distance of 5.97 A. For additional information, peptide Boc-(Ala-Delta(Z) Nap-Leu)(2)-OMe was synthesized and its solution conformation was investigated by (1)H-NMR spectroscopy. The hexapeptide showed the tendency to form a 3(10)-helical conformation in solution essentially. Conformational properties of Delta(Z) Nap residue, characterized by a type II beta-turn and 3(10)-helix, were supported by a conformational energy contour map of the Delta(Z)Nap residue.

The synthesis and structure of novel glycoside and nucleoside derivatives of phospha sugar analogs from phospholenes are reported. 1-Phenyl-2-phospholene 1-oxide was regio-and diastereo-selectively converted into a 2-bromo-3-hydroxyphospholane derivative by an action of bromine in aqueous media. The reaction of the 2-bromophospholane derivative with some amines afforded 2-amino derivatives, which were N-glycosides of phospha sugar analogs. The 2-bromophospholane derivative was also converted into the corresponding azido derivative by the replacement of the 2-bromo substituent with sodium azide. 1,3-Diploar cycloaddition of the azido derivative with alkynes afforded phospha sugar nucleoside analogs which have a triazole ring as a nitrogen heterocycle.

3-Methyl-1-phenyl-2-phospholene and 1-phenyl-2-phospholene 1-oxides were converted into 2-bromo-3-hydroxy-3-methyl-1-phenylphospholane and 2-bromo-3-hydroxy-1-phenylphospholane 1-oxide (1-bromo-1,3,4-trideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranose) by the action of bromine in aqueous medium. The bromo substituent of the phospholane was substituted by treatment with amines or an azide anion to afford novel glycoside derivatives of phosphanyl sugar analogs such as 2-amino-3-hydroxy-1-phenylphospholane (3,4-dideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranosylamine) and 2-azido-3-hydroxy-3-methyl-1-phenylphospholane 1-oxides with retention of the configuration. The 1,3-dipolar cycloaddition of the 2-azido derivative of the phospholane with alkynes gave 3-hydroxy-3-methyl-1-phenyl-2-(triazol-1′-y1)phospholane 1-oxides as a novel triazole-derived nucleoside of phosphanyl sugar analogs. The structure of the glycoside and nucleoside derivatives of the phosphanyl sugar a...

2- And 3-phospholenes were used as the starting materials for the syntheses of sugar derivatives having a phosphorus atom in the hemiacetal ring of the sugar derivatives (phosphono sugars). Alkylation or benzyloxymethylation of 3-phospholene 1-oxides afforded phospholene derivatives with more than 5 carbon atoms. Epoxidation followed by epoxide ring opening and cis-dihydroxylation of 5-benzyloxymethyl-2-phospholene derivatives afforded four pentofuranose type phosphono sugars (arabinose, lyxose, ribose, and xylose). Some nucleosides and isonucleosides of phosphono sugars were also prepared. Some of these derivatives of phosphono sugars were subjected to structure elucidation and bioassay.

Stereoselective reactions of 1-methoxy-3-phospholene 1-oxide gave a novel 1-deoxy phosphono sugar, whose relative configuration was confirmed by X-ray crystallography. Further reaction of the 1-deoxy phosphono sugar with phthalimide and 6-chloropurine produced novel phosphono sugar nucleosides.

Treatment of 1-alkoxy-3-phospholene 1-oxide with lithium diisopropylamide followed by novel stereoselective C-alkylation with alkyl halides afforded 2-alkyl-and 2-benzyloxymethyl-3-phospholene 1-oxides, which were subjected to osmium (VIII) oxide-catalyzed diastereoselective cis-dihydroxylation to give new C-glycoside derivatives of Furanose-type phosphono sugars, with twist conformation.

Optically active (S)-2-aminopropylphosphonic and (S)-2-amino-4-methylpentylphosphonic acids were synthesized from commercially available chiral α-amino acids [(S)-(+)-alanine and (S)-(+)-leucine] without racemization.

Reaction of 2-bromo-3-hydroxy-1-methoxy-3-methylphospholane 1-oxide with silylated 2-hydroxypyridine gave a novel non-natural phosphono sugar nucleoside derivative.

Reaction of 2-benzyloxymethyl-1-methoxy-3-phospholene 1-oxide with mCPBA afforded 3,4-epoxyphospholane derivatives, whose isomerized allylic alcohols were cis-dihydroxylated by osmium(VIII) oxide-catalyzed oxidation to give ribo-, arabino-, xylo-, and lyxofuranose-type phosphono sugars. The nmr data suggest a twist conformation

Treatment of 1-phenyl-2-phospholene 1-oxide with N-bromoacetamide or bromine afforded threo and erythro bromohydrins, the latter being converted into novel N-glycosides by reaction with amines. The N-t-butyl phosphono sugar glycoside exists in the 2E conformation.

4-Bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide ( 3c ) was first synthesized from 3,4-dimethyl-1-phenyl-2-phospholene 1-oxide ( 2c ) by a bromo-radical substitution reaction occurred at C-4 position by N -bromosuccinimide and 2,2′-azobisisobutyronitrile. The novel phospha sugar analogue 3c exerted high anti-proliferative effect on U937 cells evaluated by MTT in vitro methods and was much more efficient than that of Gleevec®, which is known as a molecule targeting chemotherapeutical agent. The substitution of 2-phospholenes at C-3 and C-4 position with methyl groups as well as 4-bromo substituent suggests a good anti-proliferative effect.

A new type of dendritic molecules Gd-DTPA-XDA-D1-Glc(OH), which work as a functionalized ligand coordinating gadolinium(III) ion at the center of their frameworks with two glucose moieties on the molecular surfaces, were readily synthesized with high yield. The structures were established by IR, 1 H, 13 C NMR, and mass spectral studies. Its bio-distribution patterns were evaluated on rats.

Hiroko Hasegawa, Mitsuji Yamashita,* Reiko Makita, Mayumi Yamaoka, Michio Fujie, Satoki Nakamura, Tatsuo Oshikawa, Junko Yamashita, Manabu Yamada, Mitsuru Kondo, Kazutaka Hirakawa, Mitsuo Toda, Yasuo Takehara, Kazunori Ohnishi, Haruhiko Sugimura, Sophie Laurent, and Robert N. Muller 1 Graduate School of Science and Technology, Shizuoka University, Hamamatsu 432-8561, Japan 2 Faculty of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan 3 Department of Chemistry and Biochemistry, Numazu National College of Technology, Numazu 410-8501, Japan 4 Faculty of Medicine, University of Mons, Mons, Hainaut, Belgium

Several new classes of deoxy phospha sugar derivatives, analogs of normal sugar derivatives, were conveniently synthesized using 1‐methoxy‐2‐phospholene 1‐oxide as a starting material. All compounds were structurally characterized by their spectral data, and stereochemistry was determined by spectral and X‐ray crystallographic analyses.

A novel and facile synthetic method is described in the synthesis of several deoxy phospha sugar–sugar disaccharides, analogs of normal sugar disaccharides by treatment of (±)-2-bromo-3-methoxy-1-phenylphospholane 1-oxide with several pentose and hexose sugar acetonides.

1H NMR spectroscopy of phosphorus containing hetero sugars (phospha sugars), revealed the alpha and beta configurations and chair conformations for 3-acetamido-1,4-di-O-acetyl-2,3,5-trideoxy-5-C-(isopropylphosphinyl)-alpha- and beta-D-erythro-pentopyranoses. The conformation of the title compounds was determined by 1H NMR as 1C4 in CDCl3 and the conformation was in accord with that in solid state determined by X-ray crystallographic analysis.

Optically active (S)-2-aminopropylphosphonic and (S)-2-amino-4-methylpentylphosphonic acids were synthesized from commercially available chiral α-amino acids [(S)-(+)-alanine and (S)-(+)-leucine] without racemization.

Oxidation of 3,6-di- O -benzyl-1,2- O -isopropylidene-α- d -glucofuranose with pyridinium chlorochromate in the presence of molecular sieves, followed by conversion into the p -tolylsulfonylhydrazone, addition of methyl phenylphosphinate, and reduction with sodium borohydride, provided the key intermediate, namely, 5( R , S )-3,6-di- O -benzyl-5-deoxy-1,2- O -isopropylidene-5- C -[(methoxy)phenylphosphinyl]-α- d - xylo -hexofuranose, in 23% overall yield. Treatment of this compound with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of mineral acid and acetic anhydride, yielded the crystalline title compound, the structure of which was established on the basis of mass and 400-MHz, 1 H-n.m.r. spectra. A general dependence of 2 J PH values on the OPCH dihedral angles effectively served for assigning the configuration of C-1, C-5, and the ring-phosphorus atom of the present product and other such 5- C -phosphinylhexopyranoses.

ニトロオレフィン類にH-P結合をもつリン化合物を反応させると,新たにC-P結合を形成し,β-位にニトロ基をもつリン化合物が生成した。也のニトロ基の変換は,従来のNef反応などを用いた反応では進行しなかったが,塩基存在下でのオゾンや一重項酸素との反応では進行し,アルデヒド誘導体へと高収率で変換できた。アルデヒド誘導体は還元剤によりアルコール誘導体へと変換でき,この方法により,リン糖の骨格の一部分を合成する方法が開発された。これら一連の反応を利用して若干のリン糖合成に成功した。

Treatment of 3- O -acetyl-5-deoxy-5- C -[ethyl(methoxy)phosphinyl]-1,2- O -isopropylidene-6- O -(triphenylmethyl)-α- d - xylo -hexofuranose conveniently prepared from 1,2:5,6-di- O -isopropylidene-α- d -glucose in 8 steps, with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by methanolic hydrochloric acid, and then acetic anhydride in pyridine, gave the title d -glucopyranoses in a higher overall yield than by the previous, alternative route. A minor amount of the title d -glucitol was also isolated, and characterized. Accurate 1 H-n.m.r. parameters for these ring-phosphorus-containing sugar analogs were obtained by the simulation analysis of their 400-MHz spectra.

Methyl phenylphosphonite or dimethyl phosphite underwent acid-catalyzed addition reactions with some hexofuranos-5-ulose 5-(p-tolylsulfonylhydrazones) (7, 9, and 16), to give the corresponding adducts, 17, 18, 19, and 21. The isomer ratios of the adducts were affected by a 3-substituent in the hydrazones. Treatment of adduct 21 with sodium borohydride and sodium dihydrobis(2-methoxyethoxy)-aluminate (SDMA), followed by acid hydrolysis, gave 5,6-dideoxy-3-O-methyl-5-C-(phenylphosphinyl)-d-glucopyranose (26), which was acetylated to give the 1,2,4-tri-O-acetyl derivatives 27a and 27b. Conformational analysis of compound 27a by X-ray crystallography revealed that the compound was 1,2,4-tri-O-acetyl-5,6-dideoxy-3-O-methyl-5-C-[(S)-phenylphosphinyl]-β-d-glucopyranose in the 4C1(d) form having all substituents equatorial.

2,3- O -Isopropylidene- d -ribose diethyl dithioacetal, prepared from d -ribose, was converted in three steps into the corresponding dimethyl acetal, which was monotosylated at O-5, and the ester oxidized at C-4 with pyridinium chlorochromate; addition of methyl phenylphosphinate to the resulting pentos-4-ulose derivative then provided (4 R,S )-4,5-anhydro-2,3- O -isopropylidene-4- C -[( R,S )-(methoxy)phenylphosphinyl]- d - erythro -pentose dimethyl acetal. Hydrogenation of this compound in the presence of Raney Ni, followed by reduction with SDMA, hydrolysis, and acetylation, yielded the title compounds (seven kinds), the structures of which were established on the basis of their 400-MHz, 1 H-n.m.r. and mass spectra. A general dependence of the 2 J PH and 3 J PH values on the OPCH and PCCH dihedral angles provided an effective method for the assignment of the configurations and conformations of these 4-deoxy-4-phosphinyl-pentofuranoses.

The title compounds and two diastereoisomers were prepared from (5 RS )-3- O -benzyl-5,6-dideoxy-5- C -[( RS )-(ethoxy)phenylphosphinyl]-1,2- O -isopropylidene-α- d - xylo -hexofuranoses upon reduction with sodium dihydrobis(2-methoxyethoxy)-aluminate, followed by hydrolysis with mineral acid, and acetylation with acetic anhydride-pyridine. Among these products, the two readily crystallized compounds were determined by X-ray crystallographic analysis to be 1,2,3,4-tetra- O -acetyl-5,6-dideoxy-5- C -[( S )-phenylphosphinyl]-α- and -β- l -idopyranose- 4 C 1 .

5,6-Dideoxy-6-C-nitro-5-(phenylphosphino)- d -glucopyranose was prepared by addition of phenylphosphine to 3-O-acetyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-α- d -xylo-hex-5-enofuranose, followed by hydrolysis of the resulting 3-O-acetyl-5,6-dideoxy-1,2-O-isopropylidene-6-C-nitro-5-(phenylphosphino)- d -glucofuranose (10). Acetylation of 10 gave the crystalline 1,2,3,4-tetraacetate (16). 5,6-Dideoxy-6-C-nitro-5-(phenylphosphinyl)- d -glucopyranose (15) was obtained by oxidation of 10, and hydrolysis of the resulting 5-phenylphosphinyl compound. Acetylation of 15 gave the 1,2,3,4-tetraacetate (17). Although the n.m.r. spectrum of 17 was complex, the n.m.r. spectrum of 16 was rather simple. The n.m.r. data showed that 16 is the α anomer in the 4C1( d ) conformation.

Das literaturbekannte Ribopyranosid (Ia) wird uber das Xanthogenat (Ib) wie angegeben zur 2-Desoxyverbindung (IIa) umgesetzt.